State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Gut. 2011 Apr;60(4):534-43. doi: 10.1136/gut.2010.224071. Epub 2010 Nov 10.
Hepatocellular carcinoma (HCC) is among the most lethal of human malignancies. It is difficult to detect early, has a high recurrence rate and is refractory to chemotherapies. Amplification of 1q21 is one of the most frequent genetic alterations in HCC. CHD1L is a newly identified oncogene responsible for 1q21 amplification. This study aims to investigate the role of CHD1L in predicting prognosis and chemotherapy response of patients with HCC, its chemoresistant mechanism and whether virus-mediated CHD1L silencing has therapeutic potentials for HCC treatment.
The clinical significance of CHD1L in a cohort of 109 HCC cases including 50 cases who received transarterial chemoembolisation treatment was assessed by clinical correlation and Kaplan-Meier analyses. A CHD1L-overexpressing cell model was generated and the mechanism of chemoresistance involving CHD1L was investigated. An adenovirus-mediated silencing method was used to knockdown CHD1L, and its effects on tumorigenicity and chemoresistance were investigated in vivo and in vitro.
Overexpression of CHD1L was significantly associated with tumour microsatellite formation (p = 0.045), advanced tumour stage (p = 0.018), overall survival time (p = 0.002), overall survival time of patients who received transarterial chemoembolisation treatment (p = 0.028) and chemoresistance (p = 0.020) in HCC. Interestingly, CHD1L could inhibit apoptosis induced by 5-fluorourail (5-FU) but not doxorubicin. The mechanistic study revealed that the involvement of the Nur77-mediated pathway in chemotherapeutic agent-induced apoptosis can dictate if CHD1L could confer resistance to chemotherapy. Furthermore, an adenoviral vector containing short hairpin RNAs against CHD1L (CHD1L-shRNAs) could suppress cell growth, clonogenicity and chemoresistance to 5-FU. An in vivo study found that CHD1L-shRNAs could inhibit xenograft tumour growth and increase the sensitivity of tumour cells to 5-FU in nude mice.
This study highlighted for the first time the prognostic value of CHD1L in HCC and the potential application of virus-mediated CHD1L silencing in HCC treatment.
肝细胞癌（HCC）是人类恶性肿瘤中最致命的一种。它早期难以检测，复发率高，对化疗有抗性。1q21 扩增是 HCC 中最常见的遗传改变之一。CHD1L 是一种新发现的癌基因，负责 1q21 扩增。本研究旨在探讨 CHD1L 在预测 HCC 患者预后和化疗反应、其耐药机制以及病毒介导的 CHD1L 沉默是否对 HCC 治疗具有治疗潜力方面的作用。
通过临床相关性和 Kaplan-Meier 分析，评估了 109 例 HCC 病例队列中 CHD1L 的临床意义，其中 50 例接受了经动脉化疗栓塞治疗。生成了一个 CHD1L 过表达细胞模型，并研究了涉及 CHD1L 的化学抗性机制。使用腺病毒介导的沉默方法敲低 CHD1L，并在体内和体外研究其对肿瘤发生和化学抗性的影响。
CHD1L 的过表达与肿瘤微卫星形成显著相关（p = 0.045）、肿瘤分期较晚（p = 0.018）、总生存时间（p = 0.002）、接受经动脉化疗栓塞治疗的患者的总生存时间（p = 0.028）和化学抗性（p = 0.020）。有趣的是，CHD1L 可以抑制 5-氟尿嘧啶（5-FU）诱导的细胞凋亡，但不能抑制阿霉素诱导的细胞凋亡。机制研究表明，Nur77 介导的通路参与化疗药物诱导的细胞凋亡，可以决定 CHD1L 是否可以赋予对化疗的抗性。此外，一种含有针对 CHD1L 的短发夹 RNA（CHD1L-shRNAs）的腺病毒载体可以抑制细胞生长、集落形成和对 5-FU 的化学抗性。体内研究发现，CHD1L-shRNAs 可以抑制裸鼠异种移植肿瘤的生长，并增加肿瘤细胞对 5-FU 的敏感性。
本研究首次强调了 CHD1L 在 HCC 中的预后价值，以及病毒介导的 CHD1L 沉默在 HCC 治疗中的潜在应用。
